Capsules are widely used in the pharmaceutical field as oral dosage forms for administration to humans and animals of e.g. pharmaceuticals, veterinary products, food and dietary supplements. Advantages of capsules over other conventional forms may include better patient compliance, greater flexibility in dosage form design and less expensive manufacturing process. Pharmaceutical capsules are conventionally divided into soft shell capsules (hereinafter soft capsules) and hard shell capsules (hereinafter hard capsules). The characteristics of soft and hard capsules are well known to any skilled person working in the pharmaceutical field.
For many pharmaceutical applications, e.g. when slightly or poorly water soluble substances are to be administered, it is often desirable that the substances to be encapsulated are pre-mixed with a suitable delivery carrier to form a composition which is then filled into capsules. For this reason, it is desirable that such delivery carrier be compatible with capsule shell in the sense that it must not affect capsule shell stability after filling. Typical compatibility issues that may arise are impairment of the mechanical properties of the capsule shells resulting e.g. in leaks and/or softening of the shells and/or impairment of the chemical properties of the capsule shells such as modification of shell dissolution profile.
It is known that hard capsules are often commercially preferable over soft capsules since they have a simpler manufacturing process e.g. in terms of less expertise that is generally required to operate the process, more flexibility in filling step, easier equipment operability. For these reasons, it would be desirable that a delivery carrier be compatible with hard capsules.
It is also desirable that the delivery carrier be not visually opaque or milky since this has been linked to lower patient compliance.
It is also desirable that the delivery carrier be liquid since this facilitates capsule filling step as well as gastro-intestinal release and absorption of the substance(s) after capsule shell disintegration.
It is also desirable that the liquid delivery carrier be compatible with the substances intended to be pre-mixed with it. Typically, instability can result in oxidation, hydrolysis for example over time of the substances mixed with the carrier.
U.S. Pat. No. 6,294,192, EP1158959A, EP1210063A and U.S. Pat. No. 6,451,339 disclose compositions comprising a liquid carrier for the administration of hydrophilic or hydrophobic active agents. Generally, the carriers are comprised of one hydrophilic surfactant and one hydrophobic surfactant, the former being in greater amount. These documents disclose huge lists of ingredients that can be variably combined to obtain equally effective carriers. No data are provided to infer stability of hard capsule shells after filling with such carriers.
E. T. Cole, “Liquid filled and sealed hard gelatin capsules,” Gattefossé Bulletin nr. 92 (1999), describes the use of hard gelatin capsules as an alternative for liquid/semi-solid formulations. Results from a screening program are presented based on which a list of functional excipients which are compatible with the gelatin shell is drawn up. When MCM (medium chain monoglycerides) ingredients are discussed, a suggestion is made that glycerol levels below 5% be adopted. Capmul MCM is listed in a multi-ingredient list comprising excipients incompatible with hard gelatin shells that are globally said to be usable only if admixed with compatible excipients. No suggestions are made to select a specific Capmul MCM grade nor clarifications are provided as to how Capmul MCM grade selection, its amount and the presence of further excipient would impact pharmaceutically important properties of the formulations such as transparency or viscosity.
U.S. Pat. No. 5,919,481 discloses carriers for the administration of substances (including hydrophobic ones) prone to human abuse. The aim of these carriers is to reduce the risk of drug abuse. Accordingly, these carriers must be highly viscous at room temperature so that they cannot be freely removed with a syringe. Additionally, no data are provided to infer stability of hard capsule shells in case these carriers had to be filled into hard capsules.
Thus, an object of the present invention is to provide a liquid delivery carrier that is compatible with hard capsule shells. Further objects are to provide a delivery carrier that is clear at room temperature and that is to a large extent compatible with the substances that are mixed with it before being filled into hard capsule shells.